C. M. Dougherty, R. L. Baumgarten, A. Sweeney, Jr., and E. Concepcion Herbert H. Lehman College, CUNY Bronx. New York 10468
Phthalimide, Anthranilic Acid, Benzyne An undergraduate organic laboratory sequence
Much current emphnsis in undrrgraduaw organic chemistry Irc~urecuurses involves the discussion of theoretical, spectral, and mechanistic problems. The integration of the lecture material with the experimental work in the undergraduate organic laboratory course is often a difficult task. We have incorporated the following synthetic sequence (phthalic anhydride to phthalimide to anthranilic acid to methyl anthranilate or to 1,2,3,4-tetraphenylnaphthalene)in the students' laboratory work to enhance their understanding of amine chemistry. The reaction sequence outlined above can he entered and exited at several points and the cost of the reagents used is relatively low. The reactions involved are interestine both for the theoretical, mechanistic, and synthetic concepts,and the laboratory techniques that the students learn while comoletinr! the svnthetic sequence. The conversion series as examples of amof the reactant; into the monolysis, Hofmann degradation of amides, esterification, diazotization, henzyne, and Diels-Alder reactions in the various steps in the sequence. Although the nmr spectra of the compounds are all very similar, the ir spectra are quite instructive. The change in the carhonyl group absorption in every compound can he followed easily. The change in the NH region from a broad hand with only a very small doublet in anthranilic acid (assigned to the predominance of the zwitterion structure NH3+) to a typical doublet in methyl anthranilate (assigned to pure primary amine) is easily ohserved. The first step in the reaction sequence, the conversion of phthalic anhydride to phthalimide, illustrates a typical ammonolysis reaction of an anhydride to an amide (imide). The Gabriel phthalimide synthesis is an excellent way to prepare pure primary aliphatic amines.
The next stepin the reaction sequence, the conversion of phthalimide to anthranilic acid, is an excellent example of a Hofmann degradation of an amide to an amine, and also shows the importance of p H adjustment in the precipitation of anthranilic acid, an amino acid, at its isoelectric point.
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N
A low yield of anthranilic acid is obtained if the p H is not adjusted carefully prior to precipitation. At this point in the procedure, the reaction sequence can he divided in two distinct directions. One half of the laboratory class can esterify the anthranilic acid into its methyl ester, methyl anthranilate, which is a component of oil of hitter oranges, grape juice, jasmine, and gardenias, and has an odor in dilute solutions which recalls the fragrance of orange blossoms. The ester shows a distinct blue fluorescence in the ether solutions utilized in its isolation, and a vacuum distillation can be used in its final purification. 0 .
0
II
I
C-OCH, H*
NH?
The other half of the class can convert the anthranilic acid into 1,2,3,4-tetraphenylnaphthalene,a reaction which proceeds thru a transient henzyne intermediate. Anthranilic acid is used as the precursor to generate the benzyne by conversion in situ to a diazonium salt, which spontaneously loses carbon dioxide and nitrogen, and in the presence of tetraphenylcy-
'Noyes, W. A., and Porter, P. K., Organic Synthesis, Coll. Vol. I, 457 (1932).
2The upper end of the glass rod should be inserted into a cork or ruhher stopper. This precludes any untoward accidents caused by dropping the stirring rod and breaking the bottom of flask while it is being heated with the Bunsen burner.
Volume 54, Number 10, October 1977 / 643
H
clopentadienone is converted t o t h e Diels-Alder a d d u c t ,
1,2,3,4-tetraphenylnaphthalene.
r
o
n
1
use in either of the following experiments without further purification. IR ( r ) : 2.6 and 2.8 (weak); 3.2-3.4 (weak); 5.93 (strong); 6.1-6.4 (moderate); in CH&; nmr (6): 2.09-2.27, doublet, 1H, 2.55-2.88, bmad singlet, 4H; 3.13-3.45, multiplet, 2H; in CDXCN.
1,2,3,4-Tetraphenylnaphthalenes
T h e reaction can he followed very easily since t h e reaction mixture changes from a purple solution to a yellow-orange solution when t h e t r a p is completely exhausted (similar t o a titration reaction at t h e endpoint). T h e purificatiqn utilizes trituration, a seemingly forgotten technique, h u t one which is still very useful.
Experimental Phthalimide
'
Place 50 g of phthalic anhydride and 45 ml of coned ammonium hydroxide in a 500-ml round bottom flask (Pyrex!) Fit the flask with an sir condenser (10 mm minimum i.d.1, then heat with a Bunsen hurner until the mixture is in a state of quiet fusion (temperature -:UWC). It requires-1 hr toevaporate all the water andanother hour before the mixture reaches 300°C. Shake the flask occasionally during the heating, and push down with a glass rod2 any material which sublimes into the condenser. Pour the hat reactipn mixture into a clean porcelain evaporating dish, cover with a piece of white paper to orevent lass bv sublimation. and allow to cad. Grind the cake of material obtained and storeuntil ready far the next reaction. The yield of p h t h a l i ~ i d eshould be 40-47 g; mp 232-235'C (lit.' 238°C); ir (PI: 2.7 (modelate);5.55-5.7 (strong); 7.2-7.6 (moderate);9.5 (weak); 11.0 (strong); in CH2CI2;nmr (6): 2.18, singlet, 4H; 7.70-8.18, multiplet, 1H in CDaCN.
Anthranilic AcidJ Dissolve 16.8 gof NaOH in 50 ml ofwater in a 500-ml Erlenmeyer flask and cool in an ice-salt bath until the temperatureis about 10°C. Add 250 ml of Chlaroxe (sodium hypochlorite)'and coal to below 5%. Prepare a solution of 22 g of NaOH in 80 ml ofwater and cool to below 20'C. Add 24 gof finely powdered phthalimide in one portion t o the cold, alkaline Chlorox solution, and swirl vigorously. Add the second NaOH x,lution tc, the reaction mixture, swirl vigorously, and place on the bench top. Place a thermometer in the flask to monitor temperature. The solid should dissolve as the temperature rises slowly to about 25%; the temperature then should rise rapidly to about 50°C. Heat the reaction to 80°C on a steam bath and maintain that temperature for -3-5 mi". If any undissolved material is present in the reaction mixture, filter a t this point. Cool the reaction mixture in an ice bath, then add concd HCI slowly until thereaction mixture is just slightly basie (wide range p H paper or a p H meter) (about 60 ml of' acid is required). Precipitate the anthfanilie acid by slowly adding 25 ml of glacial acetic acid (Caution: reaction mixture tends to foam a t this point). Collect the product an a Buchner funnel and wash with small portions of very cold water until the odor of acetic acid is no longer detectable. Air dry the solid until the next laboratory period. The yield of anthranilic acid should he 12-17 g; mp 142-144T (lit.V144-1459C)). If desired; the product can be decolorized (NORIT) and recrystallized from water, but it issufficiently pure to
644 / Journal of Chemical Education
Dissolve 3.84 g of tetraphenylcyelopentedienone7in 30 ml of 1.2dimethaxyethane (monoglyme) and heat toreflux in a 100-ml round bottom flask equipped with a condenser. Dissolve 1.5 gof anthranilic acid in 15 ml of 1.2-dimethoxyethane; dissolve 2 ml of isamyl nitrite" in 15 ml of 1,2-dimethoxyethane. Add these solutions simultaneously by drops to the refluring reaction mixture aver aperiod of 45min. The progress of the reaction can be monitored by the slow fading of the deep purple color of the tetraphenylcyclopentadienone;when completely reacted, the reaction mixture will turn pale orange. Evaporate the solvent by heating the reaction flask on a steam bath and simultaneously evacuating it on a water aspirator. Triturate the yellowish residue with methanol; then isolate the product on a Hirsh or small Buchner funnel. Recrystallize the product by dissolving the residue in 20 ml of a 1:l mixture of dioxane:ethanol. Heat the solution to boiling and add water by drops until a few crystals remain undissolved. Allow the product to crystallize a t room temperature before final cooling (-1 hr) in an ice bath. The yield of 1,2,3,4-tetraphenylnaphthalene should be 3.5-4.1 g; mp 196-19g°C, remelt 203-204'C (lit." 203-204°C); ir (P): 3.2 (weak);6.2 (weak); KBr pellet; nmr (6): 6.78 (singlet, 10 H); 7.18 (singlet, 10 H); 7.1-7.8 (multiplet, 4H); in CCId.
Methyl Anthranilateg
until the p H is definitely basic. Transfer the reaction mixture to a separatory funnel and extract the product into 3 X 100-ml portions of ether. Wash the combined ether extracts twice with saturated NaCl solution; then dry carefully over anhydrous NazS01. Filter, then distill off the ether. The pure ester is isolated by vacuum distillation bp 140-142°C a t 20 mm (lit.g 127°C at 11 mm); yield 4-7 g; ir (PI: 2.6and 2.8 (moderate);3.2-3.4 (weak);5.8 (strong); 6.1-6.4 (strang);as a neat liquid: nmr (6):3.72, singlet, 3H; 5.84, singlet, 2H; 6.30-6.70, multiplet, 2H; 6.95-7.25, multiplet, 1H: 7.65-7.90, multiplet, 1H; in CC14. "The preparation described here was derived from that described in Vogel, A. I., "A Textbook of Practical Organic Chemistry," 1948, p. 733. 'One can prepare the sodium hypochlorite in situ by adding 12 g of chlorine gas to a solution of 30 g of NaOH in about 80-100 ml of water. This can be done conveniently by adding chlorine gas from a tank to the NaOH solution until the weight of the solution increases by 12 gas weighed on a balance. One can also substitute sodium hypobromite (26.2 g of bromine in aqueous NaOH solution described above) for sodium hypochlorite. We have chosen to use Chlorox" for reasons of safety, economy, and purity of final product. Wouben. J., "Die Methoden der Organichen Chemie," Dritte Auflage," 1944, p. 480. Tieser, L. F., and Haddadin, M. J., Con. J. Chem., 43, 1599 119651.
(1955). 81soamyl nitrite is a powerful heart stimulant. The compound should be used in a hood or in a room with goad ventilation. T h i s preparation was derived from: Erdman, E., and Erdmsn, H., Chem Ber.. 32.1213 (18991.
general organic laboratory
